Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative disorders caused by clonally derived, skin-invasive T cells. Mycosis fungoides and Sezary syndrome are the most common types of CTCLs. Current therapies for patients with advanced disease are palliative and durable long-term remissions are rare. The poor 5-year survival of these patients using existing therapies clearly emphasizes the importance of developing new targeted therapies to treat this fatal disease. The long-term goal of this proposal is to produce a therapeutic human monoclonal antibody (Mab) that will be capable of immunodepleting malignant CTCL cells while minimizing collateral damage to an already compromised immune system. Based upon work that we have performed and published in the first funding period, our choice of target is the chemokine receptor CCR4 which is uniformly expressed at high levels on CD4+, CLA+ CTCL cells at all stages of disease. CCR4 has been demonstrated to have a critical role in the migration of memory T cells to the skin first through interactions with its ligand CCL17 on endothelial cells that mediate T cell extravasation and then with CCL22 that is expressed only in the local skin microenvironment. Over the past decade, MAb based immunotherapies have now become standard of care in a growing number of human cancers. Human MAbs can now be isolated de novo using new antibody engineering technologies that have provided a growing number of human Mabs that are in all stages of clinical trials or have already received FDA approval. In this five proposal, we will use our pioneering human antibody engineering tools to isolate a panel of high-affinity human anti-CCR4 Mabs and will conduct extensive in vitro and in vivo studies to evaluate their candidacy for the immunotherapy of CTCL. In vitro studies will be performed to delineate their mechanisms of action while in vivo studies in SCID mouse models of CTCL and in non-human primates will provide validation of their ability to cause immunodepletion of CD4+CCR4+ cells. The long-term goal of these studies is to identify one human anti-CCR4 Mab that has been selected for its ability to optimally immunodeplete CD4+CCR4+ malignant cells in vivo. As part of this proposal, we will present our timetable and plans that will result in an IND filing to conduct a phase l/ll clinical trial to evaluate anti-CCR4 Mab immunotherapy for the treatment of advanced CTCL.